Chan–Lam–Evans Coupling of Cbz-Protected Histidines
not surprisingly,[13b] in the presence of the sterically hin- ples, 31–83% yield) without epimerization. The use of these
dered 2,6-dimethylphenyl boronic acid, compound 2l was mild reaction conditions for the synthesis of pharmacologi-
obtained in lower yield (31%). Next, in light of the synthe- cally active N(τ)-(hetero)arylhistidines is currently under
sis of celogentin C,[11] various heteroaromatic boronic acids progress.
were tested in this reaction. However, a heteroatom on the
boronic acid was found to be detrimental to efficiency, and
Experimental Section
no cross-coupling product could be observed from benzo-
thiophene, (Boc- and unprotected) indoles, and quinoline
derivatives (Scheme 3). Because histidine itself is heteroaro-
matic, such a behavior is puzzling. However heterocyclic
boronic acids are known to be poorly active in Chan–Lam
coupling reactions.[14f,15g]
General Protocol for the Chan–Lam Coupling: To a solution of Z-
Hist(OMe) (1 equiv.), NaOAc (3 equiv.), and Cu(OAc)2·H2O
(0.1 equiv.) in MeOH (0.4 ) was added arylboronic acid (3 equiv.).
The mixture was heated in an open-air vessel at reflux for 24 h.
The mixture was concentrated under vacuum, and the crude mate-
rial was loaded on to a silica gel column and purified by
chromatography with a mixture of cyclohexane/AcOEt.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data of the prepared compounds, HPLC
1
traces, copies of the H and 13C NMR spectra.
Acknowledgments
We are grateful to the Centre National de la Recherche Scientifique
(CNRS) for financial support (ATIPE jeune équipe) and the Insti-
tut de Chimie des Substances Naturelles (ICSN), Gif sur Yvette,
for PhD grants (C. D. Z. and J. M.).
Scheme 3. Chan–Lam–Evans coupling reactions with heteroaro-
matic boronic acids.
[1] R. B. Herbert, Nat. Prod. Rep. 1999, 16, 199–208.
[2] A. Grauer, B. König, Eur. J. Org. Chem. 2009, 5099–5111.
[3] a) G. I. Elliott, J. P. Konopelski, Org. Lett. 2000, 2, 3055–3057;
b) J. A. Cappuccio, I. Ayala, G. I. Elliott, I. Szundi, J. Lewis,
J. P. Konopelski, B. A. Barry, O. Einarsdottir, J. Am. Chem.
Soc. 2002, 124, 1750–1760; c) K. N. White, I. Sen, I. Szundi,
Y. R. Landaverry, L. E. Bria, J. P. Konopelski, M. M. Olm-
stead, O. Einarsdottir, Chem. Commun. 2007, 3252–3254; d)
Y. R. Landaverry, K. N. White, M. M. Olmstead, O. Einarsdot-
tir, J. P. Konopelski, Heterocycles 2006, 70, 147–152.
[4] M. A. Halcrow, Angew. Chem. Int. Ed. 2001, 40, 346–349; An-
gew. Chem. 2001, 113, 358–362.
Finally, the use of potassium organotrifluoroborates was
next tested in these reactions (Scheme 4).[21] However, no
real improvement was observed (Scheme 4) in these trans-
formations and compounds 2a and 2b were obtained in 60
and 68% yield, respectively (62 and 69% yield, respectively,
from the corresponding boronic acid).
[5] a) J. Kobayashi, H. Suzuki, K. Shimbo, K. Takeya, H. Morita,
J. Org. Chem. 2001, 66, 6626–6633; b) T.-W. Leung, C. Wil-
liams, J. C. J. Barna, S. Foti, P. B. Oelrichs, Tetrahedron 1986,
42, 3333–3348; c) S. D. Kahn, P. M. Booth, J. P. Waltho, D. H.
Williams, J. Org. Chem. 1989, 54, 1901–1904; d) B. Ma, D. N.
Litvinov, L. He, B. Banerjee, S. L. Castle, Angew. Chem. 2009,
121, 6104–6107; Angew. Chem. Int. Ed. 2009, 48, 6220–6223.
[6] R. B. Bambal, R. P. Hanzlik, Chem. Res. Toxicol. 1995, 8, 729–
735.
[7] M. A. Bonin, D. Giguère, R. Roy, Tetrahedron 2007, 63, 4912–
4917 and refs cited.
[8] a) K. S. Feldman, S. Quideau, H. M. Appel, J. Org. Chem.
1996, 61, 6656–6665; b) X. Huang, R. Xu, M. D. Hawley, K. J.
Kramer, Bioorg. Chem. 1997, 25, 179–202; c) S. Deechonqkit,
S. You, J. W. Kelly, Org. Lett. 2004, 6, 497–500.
Scheme 4. Chan–Lam–Evans coupling reactions with organotri-
fluoroborates.
[9] R. Bambal, R. P. Hanzlik, J. Org. Chem. 1994, 59, 729–732.
[10] W. Yue, S. I. Lewis, Y. M. Koen, R. P. Hanzlik, Bioorg. Med.
Chem. Lett. 2004, 14, 1637–1640.
[11] J. Michaux, P. Retailleau, J. M. Campagne, Synlett 2008, 1532–
1536.
Conclusions
In conclusion, we have developed a regioselective, race-
mization-free, and efficient functionalization of protected
histidines with various aromatic boronic acids. Under
Chan–Lam–Evans conditions, using a modified and im-
proved Yu/Xie protocol [air, Cu(OAc)2·H2O, MeOH, 50 °C]
in the presence of NaOAc (3 equiv.), the cross-coupling
products were isolated in moderate to good yields (12 exam-
[12] M. W. Hooper, M. Utsnomiya, J. F. Hartwig, J. Org. Chem.
2003, 68, 2861–2873.
[13] a) A. Kiyomori, J. F. Marcoux, S. L. Buchwald, Tetrahedron
Lett. 1999, 40, 2657–2660; b) E. Alcalde, I. Dinares, S. Rodrig-
uez, C. Garcia de Miguel, Eur. J. Org. Chem. 2005, 1637–1643;
c) R. A. Altman, S. L. Buchwald, Org. Lett. 2006, 8, 2779–
2782; d) H. Zhang, Q. Cai, D. Ma, J. Org. Chem. 2005, 70,
5164–5173; e) R. A. Altman, E. D. Koval, S. L. Buchwald, J.
Eur. J. Org. Chem. 2010, 3811–3814
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3813